A family of monoclonal antibodies (mAbs) from mice that recognize oligodendrocyte (OL) surface and other central nervous system (CNS) antigens has been identified. Several of these mAbs promote remyelination in animal models of multiple sclerosis. We have now isolated related human mAbs that also promote remyelination. This family of germline autoantibodies shares characteristics with a murine mAb shown in separate studies to enhance regeneration and sprouting of CNS axons. These effects on regeneration appear to derive from blockade of growth-inhibitory molecules on the surfaces of oligodendrocytes (OL) and myelin, which normally restrict regeneration within the mammalian CNS. This combination of observations suggests that specific antibodies that enhance repair are part of the normal immunoglobulin repertoire. In addition, we hypothesize that increasing the serum concentration of these specific human proteins may provide an effective and readily implemented therapy for spinal cord injury (SCI) and related conditions. The goals of this project are to screen a panel of identified human mAbs for their ability to promote neurite outgrowth in vitro, and their ability to counteract the normally inhibitory nature of CNS myelin on neurite outgrowth. The most effective mAbs will be tested subsequently in established animal models of SCI. PROPOSED COMMERCIAL APPLICATION: The antibodies to be developed in this grant will have important applications as promoters of nerve fiber regeneration in brain and spinal cord. Chronic spinal cord injury affects more than 200,000 people in the U.S. There are no currently available therapies other than symptomatic treatments for the consequences of the condition on other body systems. Regeneration-promoting human mAbs have the potential to restore neurological function to patients with spinal cord injury and other CNS conditions that involve damage to neural pathways, providing novel therapies, with significant social, individual, and economic impact.